Sandra Zironi

Neoadjuvant Treatment With Single-Agent Cetuximab Followed by 5-FU, Cetuximab, and Pelvic Radiotherapy: A Phase II Study in Locally Advanced Rectal Cancer

PURPOSE Preoperative chemoradiotherapy followed by surgery represents the standard of care for locally advanced rectal cancer (LARC). Cetuximab has proved activity in advanced colorectal cancer, and its incorporation in preoperative treatment may increase tumor downstaging. METHODS AND MATERIALS After biopsy and staging, uT3/uT4 N0/+ LARC received single-agent cetuximab in three doses, followed by weekly cetuximab plus 5-fluorouracil (5-FU), concomitantly with RT. Sample size was calculated according to Bryant and Day test, a two-stage design with at least 10 pathologic complete remissions observed in 60 patients (pts) able to complete the treatment plan. RESULTS Forty pts with LARC were entered: male/female = 34/6; median age: 61 (range, 28-77); 12 uT3N0 Ed(30%); 25 uT3N1 (62%); 3 uT4N1 (8%); all Eastern Cooperative Oncology Group = 0. Thirty-five pts completed neoadjuvant treatment; 5 (12%) withdrew therapy after one cetuximab administration: three for hypersensitivity reactions, one for rapid progression, and one for purulent arthritis. They continued 5-FU in continuous infusion in association with RT. Thirty-one pts (77%) presented with acnelike rash; dose reduction/interruption of treatment was necessary in six pts (15%): two for Grade 3 acnelike rash, two for Grade 3 gastrointestinal toxicity, and two for refusal. Thirty-eight pts were evaluable for pathological response (one patient refused surgery, and one was progressed during neoadjuvant treatment). Pathological staging was: pT0N0 three pts (8%), pT1N0 1 pt (3%); pT2N0 13 pts (34%), and pT3 19 pts (50%) (N0:9, N1:5; N2:5); pT4 2 pts (5%). CONCLUSIONS Preoperative treatment with 5-FU, cetuximab, and pelvic RT is feasible with acceptable toxicities; however, the rate of pathologic responses is disappointingly low.

FOLFOX6 and bevacizumab in non-optimally resectable liver metastases from colorectal cancer

Background:In patients with colorectal liver metastases (CLM) R0 resection significantly improves overall survival (OS).Methods:In this report, we present the results of a phase II trial of FOLFOX6+bevacizumab in patients with non-optimally resectable CLM. Patients received six cycles of FOLFOX6+ five of bevacizumab. Patients not achieving resectability received six additional cycles of each. A PET-CT was performed at baseline and again within 1 month after initiating treatment.Results:From September 2005 to July 2009, 21 patients were enrolled (Male/Female: 15/6; median age: 65 years). An objective response (OR) was documented in 12 cases (57.1%; complete responses (CRs): 3, partial response (PR): 9); one patient died from toxicity before surgery. Thirteen patients underwent radical surgery (61.9%). Three (23%) had a pathological CR (pCR). Six patients (46.1%) experienced minor postsurgical complications. After a median 38.8-month follow-up, the median OS was 22.5 months. Patients achieving at least 1 unit reduction in Standard uptake value (SUV)max on PET-CT had longer progression-free survival (PFS) (median PFS: 22 vs 14 months, P=0.001).Conclusions:FOLFOX6+bevacizumab does not increase postsurgical complications, yields high rates of resectability and pCR. Early changes in PET-CT seem to be predictive of longer PFS.

Prognostic role of EGFR gene copy number and KRAS mutation in patients with locally advanced rectal cancer treated with preoperative chemoradiotherapy.

Background:Epidermal growth factor receptor (EGFR), evaluated by immunohistochemistry, has been shown to have prognostic significance in patients with colorectal cancer. Gene copy number (GCN) of EGFR and KRAS status predict response and outcome in patients treated with anti-EGFR therapy, but their prognostic significance in colorectal cancer patients is still unclear.Methods:We have retrospectively reviewed the baseline EGFR GCN, KRAS status and clinical outcome of 146 locally advanced rectal cancer (LARC) patients treated with preoperative chemoradiotherapy. Pathological response evaluated by Dworaks tumour regression grade (TRG), disease-free survival (DFS) and overall survival (OS) were analysed.Results:Tumour regression grade 4 and TRG3–4 were achieved in 14.4 and 30.8% of the patients respectively. Twenty-nine (19.9%) and 33 patients (19.2%) had an EGFR/nuclei ratio >2.9 and CEP7 polisomy >50% respectively; 28 patients (19.2%) had a KRAS mutation. Neither EGFR GCN nor KRAS status was statistically correlated to TRG. 5-year DFS and OS were 63.3 and 71.5%, respectively, and no significant relation with EGFR GCN or KRAS status was found.Conclusion:Our data show that EGFR GCN and KRAS status are not prognostic factors in LARC treated with preoperative chemoradiation.

Complete pathological response in a patient with multiple liver metastases from colon cancer treated with Folfox-6 chemotherapy plus bevacizumab: a case report

The complete pathological response after primary chemotherapy could represent an important prognostic factor in patients affected by colorectal liver metastases.In recent studies, increasing complete pathological response seems to be correlated with longer overall survival periods and it is recognized as an important prognostic factor in patients treated with pre-operative chemotherapy.The correlation of radiological information on residual neoplastic disease after neoadjuvant treatment, obtained with CT and PET, has to be evaluated; in fact the complete disappearance of liver metastasis on radiological imaging does not always mean a complete disappearance of tumor tissue on histological examination; when it is documented with surgical procedures and confirmed by pathologists examination, we can consider the complete pathological response.In recent years the addition of monoclonal antibodies to conventional chemotherapy may further increase the proportion of patients referred for surgery; bevacizumab before surgery has been shown to be feasible and safe, although concerns still exist regarding possible post-surgical and wound healing complications or bleeding. The limitation of the radiologic assessment of response as a surrogate for pathological response is even more relevant when antiangiogenic treatments are used. Excellent responses to bevacizumab-containing regimens do occur and referral to surgical oncology is a crucial step for documentation of complete pathological response.

591PA PHASE IB STUDY OF EVEROLIMUS, 5-FLUOROURACIL (5-FU) AND PELVIC RADIOTHERAPY (RT) AS NEO-ADJUVANT TREATMENT FOR LOCALLY ADVANCED RECTAL CANCER (LARC)

ABSTRACT Aim: The addition of 5FU to preoperative RT increases clinical downsizing and pathological downstaging and optimizes local control but has no significant effect on survival (OS). New cytotoxic drugs (irinotecan and oxaliplatin, i.e.) and targeted agents (bevacizumab and cetuximab, i.e.) have been tested in combination with 5FU and RT, but with no benefit on pathological complete response (pCR) and OS. Primary aim of the present phase Ib study is to establish the maximum tolerated dose (MTD) of everolimus in combination with 5FU and RT in LARC. Secondary: Tumor regression grade (Dworak score); rates of pCR; evaluation of biological parameters of inhibition of target (tissue expression of phosphorilated S6 and mTOR) before, after 2 weeks of treatment (before concomitant treatment) and on surgical specimen. Methods: Between march 2011 and december 2013 12 patients with histologically confirmed diagnosis of LARC (T3-T4; N0-1; within 15 cm from anal rhyma) were enrolled at University Hospital of Modena. Pts have been sequentially assigned to one of the following 4 cohorts and have been administered with the following dose levels: everolimus at 2,5 mg; 5 mg; 7,5 mg; 10 mg daily per os starting from 14 days before 5FU and RT and for all the duration of the concomitant treatment. DLT was defined as every reported toxicity (haematological and non haematological) ≥ grade 3, as defined by CTC criteria 3.0. Grade 2 pneumonitis lasting more than 7 days or recurrent on the same cycle or grade > 3 of any duration. Results: Twelve pts have been treated and no DLT (as defined above) was recorded. The reported toxicities were: skin rash (observed in 3 cases: 2 G1 and 1 G2), asthenia (observed in 4 cases, G1), diarrhea (observed in 6 cases: 5 G1 and 1 G2), mucositis (observed in 1 case, G1) and urinary disfunction (observed in 4 cases, G1; probably related to pelvic radiotherapy). Only one pt underwent Miles surgical resection (8%). Dworak TRG was as follows: TRG 0-1-2 = 10/12 (83%); TRG 4 (pathological complete response) = 2/10 (17%). No TRG3 was recorded. Conclusions: Combination of everolimus, 5FU and RT is feasible. We observed ≥15% of patients with TRG 3-4; the combination will be considered for a phase II trial. Biological parameters evaluation is still ongoing. Disclosure: All authors have declared no conflicts of interest.